Process for producing 3-keto-delta-steroids



.positions of steroid compounds.

Un ed Y States Pate PROCESS FOR PRODUCING 3-KETO-A STEROIDS Walter T. Moreland, New London, Conn., and Eugene J. Agnello, Jackson Heights, N.Y., assignors to Chas. Pfizer & Co., Inc., Brooklyn, N.Y., a corporation of Delaware No Drawing. Application August 18, 1958 Serial No. 755,420

7 Claims. (Cl. 260-23955) This invention is concerned with an improved process for producing 3keto-A -steroid compounds from 3-keto A-ring saturated, 3-keto-A and 3-keto-A -steroids.

Various methods have been utilized in the past for the introduction of double bonds at the 1,2-, 4,5- and 6,7-

For example, 3-keto compounds have been treated with bromine to introduce .bromine at the 2- and/ or 4-positions, or with N-bromolarger scale it leads to the formation of grossly impure products which are not amenable to purification by any known means. In particular, they contain major proportions of the 3-keto-A -analogs resulting from incomplete dehydrogenation. This is true even where a large excess of the quinone is employed.

It has now been discovered that it is possible to prepare 3-keto-A -compounds of high purity on any scale, provided certain critical conditions are employed. According to this novel process, the 3-keto steroid is treated with a quinone having an oxidatiomreduction potential of less "than about 0.5 at a temperature of from about 110 C. to about 155 C. in an alcohol solvent in the presence of an additive selected from the group consisting of sub' divided calcium carbonate, strontium carbonate, metallic germanium, and glass. Most unexpectedly, however, no

improvement is observed if diatomaceous earth or activated carbon is employed in place of the enumerated additives. Even more surprising is the fact that while calcium carbonate is effective, barium carbonate is not.

The solid additives employed to promote the reaction of this invention should be particulate; that is, they should be in the form of subdivided particles. For example, while glass helices or ground glass are employed with success, it is not sufiicient merely to employ a glass-lined ,reaction vessel. However, effectiveness of the added solid does not vary appreciably with particle size. Thus, powdered calcium carbonate having a particle diameter of less than microns may be utilized with success, but the coarse product commonly known as marble chips and having "a particle diameter in excess of one centimeter is likewise elfective. The most desirable particle size will ordinarily be determined by the size and dimensions of the equipment employed. Thus, it may be found most economical to employ the less expensive, larger particles in large equipment, while in small equipment it is sometimes desirable to use smaller particles so as to decrease 2,883,379 Patented Apr. 21, 1959 obtained with at least about 1% by weight of the reaction mixture, and it is generally unnecessary to use more than about 20% by weight. Of course, more than this can be employed but ordinarily no more will be used than is required to fill the reaction vessel to the liquid surface.

The reaction temperature employed in the process of this invention may range from about C. to about 155 C., preferably from about C. to about C. At temperatures much below 110 C. the reaction will usually not go to completion, whereas at temperatures much above C. side reactions and decomposition are likely to occur.

The solvent employed in the process of this invention is preferably a saturated aliphatic alcohol of up to nine carbon atoms containing primary or secondary alcohol groups. It is convenient to employ an alcohol having a boiling point at atmospheric pressure of from about 110 C. to 155 C., the preferred range of reaction temperature, but this is not essential. Thus, an alcohol boiling below 110 C. may be employed for reaction in a pressure vessel and, likewise, an alcohol boiling above 155 C. may be utilized below its boiling point. Among the alcohols which may be employed for this invention are propanol-l, 2-methyl-propanol-l, 2-methyl-butanol-4, pentanol-l, hexanol-l, Z-ethyI-butanol-l, Z-ethyl-hexanol-l, pentanol-2, 2-methyl-butanol-3, pentanol-3, 4 methyl-pentanol-Z, and their mixtures.

Quinones used in carrying out the process of this invention are those which under standard conditions have oxidation-reduction potentials of less than 0.5, and preferably those having potentials of 0.65 or less. Oxidation-reduction potentials are readily determined by reference to standard scientific texts (see Handbook of Chemistry and Physics, 31st edition, p. 1442, Chemical Rubber Co., 1949, and Latimer and Hildebrand, Reference Book of Inorganic Chemistry, revised edition, pp. 474-481, Macmillan, 1940). Quinone itself (also known as benzoquinone), chloranil, 2,6-dichlorobenzoquinone, toluquinone, 1,2-naphthoquinone, hydroquinone and xyloquinone are among those successfully employed in this process.

The quantity of the quinone is not critical. Although a minimum of one mole is theoretically required for each double bond introduced, some of the desired product is nonetheless produced even with less than one mole. Ordinarily from about one to about three moles of the quinone will be employed for each double bond introduced, and preferably from about 1.1 to about 1.5 moles. For example, in the conversion of a 3-keto-A to a 3-keto- A -steroid from about two to about six moles of the quinone will be usually employed, the preferred quantity being from about 2.2 to about 3. Even more than three moles of the quinone can be employed for each double bond introduced, but ordinarily any increase in yield thereby attained is not sufiicient to justify the added expense.

The starting materials for the present process are known compounds which are obtainable by a variety of procedures described in the chemical literature. The 3-ketosteroid compounds used as starting materials contain from 18 to 21 carbon atoms and may be substituted with a variety of groups. For example, they may contain hydroxyl groups at the 11,14,16,17 and/or 21-positions; keto groups at the 11,17 and/or 20-positions; methyl groups at the 2,6 and/or 16-positions; halogen at the 15,16 and/or 21-positions; an acyloxy group at the 21- position. The steroids may contain double bonds at the 4,5; 6,7; 9,11; or 14,15-p0sitions, or certain combinations 'stirring mechanism. The quantity of solid additive em ployed ,is not critical, although best results are usually of these. They may contain epoxy groups at the 9,11 and/ or the 14,15-positions.

Among the compounds which may be prepared by this novel process are: A -pregnatriene-17a,21-dio1-3,20-

. A -pregnatetraene-11,8,17a,2l-triol-3,20-dione; A

androstatriene-17B-ol-3-one; A -androstatriene-3 1 1,17- trione; and the esters of those compounds having a 21- Jhydroxyl group or if a derivative of androstene, a 17-hydroxyl group. These esters include, for example, the

'benzoates, acetates, propionates, butyrates, hemisuccinates, and other hydrocarbon carboxylic acid groups having from one to ten carbon atoms.

Compounds prepared by the process of this invention .are useful for various therapeutic purposes. For example,

the A -bisdehydro analogs of cortisone and hydrocortisone have valuable anti-inflammatory action when administered to animals, including humans. Others are derivatives of progesterone and possess similar activity. Derivatives of androstene are useful in correcting nitrogen imbalance after serious injury or surgery.

The 9,1l-oxido compounds prepared by this process do not possess appreciable therapeutic activity. They are, however, valuable intermediates for the preparation of therapeutically active 9ct-halo-l1B-hydroxy compounds by treatment with halogen acids according to known procedures.

In the operation of this new process the 3-keto steroid compound which is to be used as a starting material is placed in a solvent of the type described and the selected quantity of the quinone is introduced. Subdivided calcium carbonate, strontium carbonate, germanium, or glass is then added to the mixture in the reaction vessel. If the solvent chosen is one which produces a reaction mixture boiling below about 110 C. the vessel employed will be one suitable for operation under superatmospheric pressure. An agitator or other means for suspending the subdivided solid in the reaction mixture is preferably provided. However, if the solvent selected is such that the reaction is conveniently conducted at the boiling point of the reaction mixture, additional means for agitation may often be omitted.

The mixture is then heated to a temperature of from about 110 C. to about 155 C., and, most conveniently, at the boiling point of the solvent if it boils within this range. The reaction may be carried out in an inert atmosphere, for example, under nitrogen, to minimize decomposition of the starting material and product, although this is not essential. The duration of the reaction is not critical, since some product forms almost immediately, but optimum results are usually obtained in from about one-half to about six hours, and from about one to about three hours is often adequate.

Equivalent procedures for carrying out the process of this invention will be apparent to those skilled in the art. For example, a heated solution of the 3-keto steroid compound and the quinone, in a solvent of the type described, may be passed over the particulate solid contained in a column.

The product of the dehydrogenation reaction may be isolated by any of a number of means apparent to those skilled in the art. For example, the added solid is usually first separated, by filtration or decantation, and, if desired, reserved for washing and reuse. The

solvent is then removed by evaporation or steam-distillation, preferably under reduced pressure. thus obtained may be-further purified by extraction with The product washed and concentrated to 125 ml.

atmospheric or reduced pressure to obtain the desired product.

Some of,.the advantages of this novel process will be better understood by reference to the table below, in which the conversion of hydrocortisone acetate to the corresponding A andih ecompounds with chloranil is reported.

Product Composition Added Solid 'All ALG none" 60 40 C110 03 15;1) 95 CaOO (ca. 1 cm. 95 SrOOw 95 CaC 0 1 l l 95 glass helices (35 g.) 10 CaC 0 10 90 Germanium (1 g.)" 3 97 1g. acetate, 1.5 g. chloranil; 5g." added .solid,i.n. 35' m1. isoamyl alcohol, refluxed 1% hrs.

As in with n-hexanol' in place of isoamyl alcohol.

Thefollowing examples are-givenbyway of illustration and'are'not to be'regarded as limitations of this stirred an .additional30 minutes. i The reaction mixture is then filtered, concentrated .under reduced pressure,

and steam-stripped in vacuum until only water distills. Theaqueous residue is cooled and extracted with 1250 ml. methylenechloride. This mixture is clarified with a.filter-aid and the cake is extracted with fresh methylene chloride. The combined methylene .chloride extracts are washed with 5% potassium hydroxide until no more color canbe removed, and then with aqueous acetic acid and with water. The methylene chloride solution is then filtered and concentrated to 745 ml. 'In order to reacetylate any product which may have'been hydrolyzed bythe alkaline wash, the concentrate is next treated with pyridine :=and .acetic anhydride. After standing overnight the mixture is washed with hydrochloric acid to remove the pyridine, and then is water- 500 ml. benzene is added and the concentration is continued to a head temperature of 7880 C. The product is isolated from the benzene slurry by filtration. After benzene-washing and vacuum-drying 30.8 g. (a 62% yield) of high-purity product melting at 207-210.2 C. is obtained. The ultra violetspectrum shows 21x33? 223 my, (6 12,500), 255 [up (69,600), 300 my.

When the experiment is repeated omitting the calcium carbonate, less than a 5%yield of the desired product is obtained in admixture-with'an equal'quantity of the 3-keto-A -analog.

EXAMPLE II 9,3,11fl-oxido-A '@pregnatriene-1 7a,21-di0l-3,20-di0ne ZI-acetate 1 g. 95,1lfl oxido-A' -pregnene l7a,21-diol3,20 dione Zl-acetate is treatedasin Example 'I with'appropriate changes in scale. The product is0'.-25 g. (25% yield) of nearly white 'powder,'M.P. -211223 C. The ultraviolet spectrum shows X \1 :2F.220223 [1111(6-11300), 259-264 my (6 11,500),

5 When the experiment is repeated omitting the calcium carbonate, the product obtained contains a major proportion of the 3-keto-A -analog.

7 EXAMPLE In A -pregnatriene-1 1 5,1 70:,21 -triol-3,20-dine 21-acetate l g. A -pregnene-1 lfi,17a,21-triol-3,20-dione Zl-acetate, 3 g. chloranil and 1 g. germanium metal (pulverized) in 35 ml. mixed sec.-amyl alcohols are refluxed for 3 hours. (The solvent can be obtained from the Matheson Coleman and Bell Company.) Purification as in Example I gives the desired product.

EXAMPLE IV A -androstatriene-l 7B-0l-3-0ne 17-acetate with ether yields a yellow crystalline product melting at 142148 C. The ultraviolet spectrum shows M12? 220 m (6 11,400), 251-257 mp (e 10,400), 295-301 my (6 12,000) Concentration of the filtrate yields a second crop of product.

When the experiment is repeated omitting the calcium carbonate, the product obtained contains a major proportion of the 3-keto-A -analog.

EXAMPLE V A -pregnatriene-1 7m,21-diol-3,20-di0ne 21-acetate A A mixture of 2 g. A pregnene-17a,21-diol-3,20-dione 21-acetate, 3.5 g. 2,6-dichlorobenzoquinone, and 75 g. glass beads in 80 ml. pentanol-l is refluxed for 180' minutes. The reaction mixture is then filtered, concentrated in vacuum and vacuum-steam-stripped until shortly after a single-phase distillate begins to collect. The residue is cooled and extracted with methylene chloride. The extract is then washed with a potassium hydroxide solution, with aqueous acetic acid, and with water. Evaporation of the methylene chloride yields the desired product substantially free of the 3-keto-A analog.

EXAMPLE VI A -pregnatriene-l15,1 70:,21 -tri0l-3,20-dione 21-acetate A -pregnadienedlfl,17a,21-triol-3,20-dione 21-acetate is prepared from A -pregnene-1l,B,17a,21-t1iol-3,20-dione 21-acetate by refluxing with chloranil in 2-methyl propanol-2. A mixture of 5 g. of the A -compound, 6 g. chloranil and 25 g. calcium carbonate in 200 ml. propanol-l is heated at 130 C. with stirring in a pressure vessel for 180 minutes. The contents of the vessel are cooled, filtered, and the filtrate is concentrated to a heavy syrup under reduced pressure. The concentrate is extracted with methylene chloride and filtered. The filtrate is then washed free of colored impurities with aqueous 5% potassium hydroxide, followed by dilute acetic acid and water. It is then concentrated to a small volume and benzene is added. Distillation is continued until the vapor temperature is 78-80 C. The resulting slurry is cooled and filtered to obtain the desired solid product in high purity.

EXAMPLE VII A -pregnatriene-1 7m,21-di0l-3,11,20-tri0ne ZI-propionate A mixture of 2 g. of A -pregnene-17a,21-diol-3,-11,20- trione 21-propionate, 3.5 g. 2,6-dichlorobenzoquinone, and 75 g. glass helices in 80 ml. pentanol-l is refluxed .butanol-3 is refluxed for 75 minutes.

6 for 180 minutes. The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-keto-A -analog.

EXAMPLE VIII A -pregnatriene-I1,8,21-di0l-3,20-di0ne A mixture of 2 g. A -pregnene-1lfi,21-dio1-3,20-dione, 2 g. benzoquinone, and 10 g. strontium carbonate in ml. Z-methyl butanol-4 is refluxed for 75 minutes. The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-keto-A analog.

EXAMPLE IX A -pregnatriene-3,20-dione A mixture of 2 g. A -pregnene-3,20-dione, 2 g. benzoquinone, and 10 g. strontium carbonate in 80ml. 2- methyl butanol-4 is refluxed for 60 minutes. The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-ket0-A -analog.

EXAMPLE X 2-methyl-A -pregnatriene-1 1;3,17tx,21-tri0l-3,20-di0ne 21 -acetate A mixture of 2 g. 2-methyl-A -pregnene-11B,17u,2ltriol-3,20-dione ZI-acetate, 2.5 g. chloranil, and 10 g. calcium carbonate in 80 ml. propanol-l is heated at 150 C. with stirring in a pressure vessel for 30 minutes. The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-keto- M' -analog.

EXAMPLE XI 6-methyl-A -pregnatriene-I 70:,21-di0l-3,11,20-tri0ne 21 -butyrate A mixture of 2 g. 6-methyl-A -pregnene-17a,2l-diol- 3,11,20-trione 2l-butyrate, 3 g. chloranil, and 10 g. calcium carbonate in 80 ml. 2-methyl propanol-l is heated at C. with stirring in a pressure vessel for 75 minutes. The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-keto-A -analog.

EXAMPLE )(II A -androstatriene-3J1,1 7 -tri0ne A mixture of 2 g. androstane-3,11,17-trione, 4.5 g. chloranil, and 10 g. calcium carbonate in 80 ml. 2-methyl The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-keto-A -analog.

EXAMPLE XIII A -pregnatrien e-1 1 5,14 7 a,21 -tetrol-3,20-di0ne 21 -acetate A mixture of 2 g. A -pregnene-l1B,14a,17u,21-tetrol- 3,20-dione 2l-acetate, 5 g. chloranil, and 0.7 g. germanium in 80 ml. propanol-l is heated at C. with stirring in a pressure vessel for 60 minutes. The reection mixture is then treated as in Example V to recover the product, substantially free of the 3-keto-A -analog.

EXAMPLE XIV 14a,15a-0xid0-A -pregnatriene-1 701,21 -di0l- 3,11,20-tri0ne A mixture of 2 g. 14a,15a-oxido-allopregnane-17a,2ldiol,3,11,20-trione, 4.5 g. chloranil, and 10 g. calcium carbonate in 80 ml. 4-methyl pentanol-Z is refluxed for 120 minutes. The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-keto-A -anal0g.

"with stirring for 75 minutes. then treated as in Example V to recover the product,

7 "EXAMPLE. XV

"A -pregnatetraene-11fl,17a,21 -tri'ol-3,20-dione 21 -benz0ate A mixture of 2 g.' A pre"gnene-115,17a,21-triol3,20- dione 21-benzoate, 2 g. hydroquinone, and g. calcium carbonate in-"SO m1. '2-methyl butanol-4 isrefiuxed for 75 :minutes. The reaction mixtureisthen treated as in Example V to recover the product, substantially free of the 3-keto-A -analog.

EXAMPLE XVI A -pregnatetraene-l 711,21 -di0l-3,20-dione 21 acetate A mixture of 2 g. A -allopregnene-l7a,21-di0l-3,20- dione Zl-acetate, 7 g. chloranil, and g. calcium carbonate in 80 ml. 2-ethyl'he'xanol-1 is heated at 150 C. The reaction mixture is substantially free of the 3-keto-A analog.

EXAMPLE XVII A -pregnatriene-I 1 8,1 6a,21 -tri0l-3,20-di0ne 21-acetate A mixture of 2 g. A -PICgI1GH6-I1B,16x,21-t1'i01-3,20- dione 21-acetate, 3 g. chloranil, and 10 g. calcium carbonate in 80 mlvpentanol-2 is heated .at 140 C. with stirring in a pressure vesselfor 180 minutes. The reaction mixture is then treated as in Example V to recover the product, substantially free of the 3-keto-A -analog.

EXAMPLE XVIII 16/9-chZora-A -pregnatriene-I 70:,21-di0l-3,11;20-tri0ne 1 21 -acetate A mixture of 2g. 1fifi chloro-A -pregnene-170:,21-di0l- 3,11,20-trione ZI-acetate, 3 .g.'chloranil, and 10 g. calcium carbonate in 80 ml. Z-methyl butanol-4is heated at 140 C. with stirring in a pressure vessel for 180 minutes. The reaction mixture is then treated as in Example V to recover theproduct, substantially free of the 3-keto- M' -analog.

What is claimed is:

1. An improved process for the production of a 3-keto- A -steroid compound having from 18 to 21 carbon atoms in thesteroidnucleus, *which comprises reacting a compound selected from the group consisting of 3-keto A ring saturated, 3-ketoA and 3-keto-A -steroids, with aquinone having an oxidation-reduction potential of less than about O.5, at a temperature of from about C. to about C. in a solvent selected from the group chloranil.

-3. A process as in claim 1 wherein the quinone is 2,6-

- dichlorobenzoquinone.

4. A process as in claim 1 wherein the quinone is benzoquinone.

5. A process as in claim 1 wherein the alcohol is -propanol-1.

6. A processas in claim 1 wherein the alcohol is 2- methyl butanol-4.

7. In'the process of preparing a 3keto-A -steroid compound having from 18 to 21 carbon atoms in the steroid nucleus by oxidation of a compound selected from the .group consisting of 3-keto A-ring saturated, 3-keto- A and 3-keto-A -steroids by a quinone having an oxidati'on-reduction potential of less than about -05, at a temperature of from about 110 C. to about 155 C. in a solvent selected from the group consisting of primary and secondary alkanols containing up to nine carbon atoms, the improvement which comprises carrying out the process in the presence of a particulate solid selected from the group consisting of calcium carbonate, strontium carbonate, germanium and glass.

No references cited. 

1. AN IMPROVED PROCESS FOR THE PRODUCTION OF A 3-KETO*1,4,6-STERIOD COMPOUND HAVING FROM 18 TO 21 CARBON ATOMS IN THE STERIOD NUCLEUS, WHICH COMPRISES REACTING A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3-KETO A-RING SATURATED, 3-KETO-*4, AND 3-KETO-*4,6-STERIODS, WITH A QUINONE HAVING AN OXIDATION-REDUCTION POTENTIAL OF LESS THAN ABOUT -0.5, AT A TEMPERATURE OF FROM ABOUT 110* C. TO ABOUT 155*C. IN A SOLVENT SELECTED FROM THE GROUP CONSISTING OF PRIMARY AND SECONDARY ALKANOLS CONTAINING UP TO NINE CARBON ATOMS, IN THE PRESENCE OF A PARTICULATE SOLID SELECTED FROM THE GROUP CONSISTING OF CALCIUM CARBONATE, STRONTIUM CARBONATE, GERMANIUM AND GLASS. 